Laboratório de Microbiologia Molecular e Clínica, Universidade São Francisco, Bragança Paulista, Brazil.
Programa de Pós-Graduação Interunidades em Biotecnologia-USP-IPT-IB, São Paulo, Brazil.
PLoS One. 2022 Dec 7;17(12):e0277304. doi: 10.1371/journal.pone.0277304. eCollection 2022.
PspA and pneumolysin are two important vaccine candidates, able to elicit protection in different models of pneumococcal infection. The high immunogenic potential of PspA, combined with a possible adjuvant effect of pneumolysin derivatives (due to their ability to interact with TLR-4) could greatly improve the immunogenicity and coverage of a protein-based pneumococcal vaccine. A chimeric protein including the N-terminal region of PspA in fusion with the pneumolysin derivative, PlD1, has been shown to induce high antibody levels against each protein, and protect mice against invasive challenge. The aim of the present study was to investigate the cellular response induced by such vaccine, and to evaluate protection in a murine model of lobar pneumococcal pneumonia. Pneumococcal pneumonia was induced in BALB/c mice by nasal instillation of a high dose of a serotype 14 strain with low virulence. Airway inflammation was confirmed by total and differential cell counts in BAL and by histological analysis of the lungs, and bacterial loads were measured 7 days after challenge. Cytokine levels were determined in the bronchoalveolar fluid (BALF) of mice immunized with rPspA-PlD1 fusion after challenge, by flow cytometry and ELISA. After challenge, the mice developed lung inflammation with no invasion of other sites, as demonstrated by histological analysis. We detected significant production of TNF-α and IL-6 in the BALF, which correlated with protection against pneumonia in the group immunized with rPspA-PlD1. In conclusion, we found that the rPspA-PlD1fusion is protective against pneumococcal pneumonia in mice, and protection is correlated with an early and controlled local inflammatory response. These results are in agreement with previous data demonstrating the efficacy of the fusion protein against pneumococcal sepsis and reinforce the potential of the rPspA-PlD1 protein chimera as a promising vaccine strategy to prevent pneumococcal disease.
PspA 和肺炎球菌溶血素有两种重要的疫苗候选物，能够在不同的肺炎球菌感染模型中引起保护作用。PspA 的高免疫原性，结合肺炎球菌溶血素衍生物（由于其与 TLR-4 相互作用的能力）的可能佐剂效应，可能极大地提高基于蛋白质的肺炎球菌疫苗的免疫原性和覆盖范围。一种嵌合蛋白，包括 PspA 的 N 端区域与肺炎球菌溶血素衍生物 PlD1 融合，已被证明能诱导针对每种蛋白的高抗体水平，并能保护小鼠免受侵袭性挑战。本研究的目的是研究这种疫苗诱导的细胞反应，并在肺炎球菌性肺炎的小鼠模型中评估保护作用。通过鼻腔滴注低毒力 14 型血清型的高剂量细菌，在 BALB/c 小鼠中诱导肺炎球菌性肺炎。通过 BAL 中的总细胞计数和差异细胞计数以及肺部组织学分析来确认气道炎症，并在挑战后 7 天测量细菌负荷。通过流式细胞术和 ELISA 测定用 rPspA-PlD1 融合免疫后的小鼠支气管肺泡液（BALF）中的细胞因子水平。挑战后，组织学分析显示，小鼠肺部发生炎症，但没有其他部位的侵袭。我们在 BALF 中检测到 TNF-α和 IL-6 的显著产生，这与免疫 rPspA-PlD1 组对肺炎的保护作用相关。总之，我们发现 rPspA-PlD1 融合蛋白对小鼠肺炎球菌性肺炎具有保护作用，保护作用与早期和受控的局部炎症反应相关。这些结果与先前证明融合蛋白对肺炎球菌败血症有效性的数据一致，并加强了 rPspA-PlD1 蛋白嵌合体作为预防肺炎球菌疾病的有前途的疫苗策略的潜力。
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